THE RECEPTOR OF SERPENTINE TYPE AND THE HETEROTRIMERIC G PROTEIN AS TARGETS OF ACTION OF THE POLYLYSINE DENDRIMERS
A. O. Shpakov,1 I. A. Guryanov,2 N. V. Bayanova,2 G. P. Vlasov 2
1 I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, and 2 Institute of Macromolecular Compounds RAS,
St. Petersburg;
e-mail: alex_shpakov@list.ru
The molecular mechanisms of action of the polycationic peptides - polylysine homo- and heterodendrimers on functional activity of biogenic amines- and peptide
hormones-sensitive adenylyl; cyclase signaling system (AC system) in the myocardium and the brain of rats were studied. These peptides are expected to be used
as highly effective polymer carries for biologically active substances. The polylysine homodendrimers of the third
[(NH2)16 (Lys)8(Lys)4(Lys)2Lys-Ala-NH2] (I), fourth
[(NH2)32(Lys)16(Lys)8(Lys)4(Lys)2Lys-Ala-NH2] (II) and firth
[(NH2)64(Lys)32(Lys)16(Lys)8(Lys)4(Lys)2Lys-Ala-NH2]
(III) generations and the polylysine homodendrimers of firth generation -
[(NH2)64(Lys-Glu)32(Lys-Glu)16(Lys-Glu)8(Lys-Glu)4(Lys-Glu)2Lys-Ala-Ala-Lys(ClAc)-Ala-NH2] (IV),
[(NH2)64(Lys-Ala)32(Lys-Ala)16(Lys-Ala)8(Lys-Ala)4(Lys-Ala)2Lys-Ala-Lys(ClAc-Ala-Ala-NH2)] (V) and
[(NH2)64(Lys-Gly-Gly)32(Lys-Gly-Gly)16(Lys-Gly-Gly)8(Lys-Gly-Gly)4(Lys-Gly-Gly)2Lys-Gly-Gly-Lys(ClAc)-Ala-Ala-NH2] (VI)
showed receptor-independent mechanism of heterotrimeric G-proteins activity, preferably of inhibitory type, interacting with C-terminal regions of their α-subunits.
The homodendrimers II and III and heterodendrimer V are more effective G-protein activators. The polylysine dendrimers disturbed the functional coupling of the
receptors of biogenic amines and peptides hormones with Gi-proteins and, in a lesser extent, Gs-proteins. This is illustrated by the
decrease in regulatory effects of the hormones on AX activity and G-protein GTP binding and by the decrease in receptor affinity to agonists in the presence of the
polylysine dendrimers, as result of receptor-G-proteins complex dissociation. It was shown also that the molecular mechanisms and the selectivity of the action on
the G-proteins of the polylysine dendrimers were similar to those of mastoparan and melittin, natural toxins of insect venom.
Key words: adenylyl cyclase, adrenergic receptor, heterotrimeric G protein, GTP binding, mastoparan, polylysine dendrimer, serotonin receptor
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